[go: up one dir, main page]

WO2021115882A1 - Implants revêtus et leurs procédés de fabrication - Google Patents

Implants revêtus et leurs procédés de fabrication Download PDF

Info

Publication number
WO2021115882A1
WO2021115882A1 PCT/EP2020/084301 EP2020084301W WO2021115882A1 WO 2021115882 A1 WO2021115882 A1 WO 2021115882A1 EP 2020084301 W EP2020084301 W EP 2020084301W WO 2021115882 A1 WO2021115882 A1 WO 2021115882A1
Authority
WO
WIPO (PCT)
Prior art keywords
coating
substrate
implant
optionally
ceria
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2020/084301
Other languages
English (en)
Inventor
Tino Matter
Inge Katrin HERRMANN
Sotiris Pratsinis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eidgenoessische Technische Hochschule Zurich ETHZ
Eidgenoessische Materialpruefungs und Forschungsanstalt
Original Assignee
Eidgenoessische Technische Hochschule Zurich ETHZ
Eidgenoessische Materialpruefungs und Forschungsanstalt
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eidgenoessische Technische Hochschule Zurich ETHZ, Eidgenoessische Materialpruefungs und Forschungsanstalt filed Critical Eidgenoessische Technische Hochschule Zurich ETHZ
Publication of WO2021115882A1 publication Critical patent/WO2021115882A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/306—Other specific inorganic materials not covered by A61L27/303 - A61L27/32
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/06—Titanium or titanium alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/10—Ceramics or glasses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/32—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates to coatings and its uses as well as processes of making such coatings.
  • the coatings are characterized by their chemical composition and architecture; they are antimicrobial, tissue regenerative and tissue bonding, making them useful as a coating of an implant.
  • Manufacturing processes for such coating combine flame spray pyrolysis and direct coating of a substrate; the process uses inexpensive starting materials and is scalable .
  • FSP Flame Spray Synthesis
  • WO2004/005184 discloses the synthesis of metal oxides via FSP.
  • the thus obtained nanoparticulate material may be used in catalytic applications.
  • WO2005/087660 discloses the synthesis of metal salts, particularly calcium phosphate, via FSP.
  • the thus obtained nanoparticulate material is biocompatible and osteoconductive and may be used in medical applications.
  • WO2011/020204 discloses the synthesis of radio-opaque bioactive glass materials via FSP.
  • the thus obtained nanoparticulate material may be used in dental fillings.
  • the FSP methods disclosed in these documents are suitable for a wide range of applications, but fail to prepare structured coatings as described herein.
  • Matter et al disclose flame-made ceria/bioglass hybrid nanoparticles and their use for tissue engineering.
  • FSP allows tailoring the architecture and the properties of the nanoparticles.
  • bioglass in combination with ceria, loses its bioactivity, due to the inhibition of bioglass mineralization by ceria.
  • the document is silent on any coating of the as-produced material .
  • US2005/0176843 described dental composites based on FSP made nanoparticles. These composites are introduced into dental cavities or applied on the surface of teeth.
  • Implants for medical applications are well-known. It is generally accepted to improve their performance by partially or fully coating their surface.
  • WO2017/062573 discloses nanoceria coated implants to reduce osteolysis.
  • the coating is obtained by wet-phase synthesis. Although suitable, the manufacturing of such coatings is difficult to control and thus less suited for commercial manufacturing. The manufacturing disclosed therein fails to prepare structured coatings as described herein .
  • WO2017/031524 discloses porous crystalline hydroxyapatite films.
  • the films may be obtained by FSP and may be used to manufacture a prosthesis. Although suitable, the films disclosed in that document suffer from limited bioactivity and slow resorption rate.
  • an object of the present invention is to mitigate at least some of these drawbacks of the state of the art.
  • Such superior properties may be achieved by one or more of the following (i) better cell attachment on the implant, (ii) decreased foreign body reaction and inflammation (iii) higher cyto- compatibility and/or (iv) preventing formation of biofilms on the implant.
  • These objectives are achieved by a coating as defined in claim 1; an implant as defined in claim 6 and its manufacturing as defined in claim 10.
  • stable and diverse nanoparticle coatings are provided; they are obtainable by using fast, inexpensive and scalable flame-spray pyrolysis.
  • inventive implants allow improved cell adhesion on their surface. Without being bound to theory, it is believed that this beneficial effect is due to the high compatibility of the inventive coatings with gingival fibroblasts .
  • inventive implants prevent infections after implantation.
  • incorporation of ceria into the coating supports antimicrobial properties.
  • the "diameter" of a particle as described herein is the volume-surface-average diameter of the primary particle. This may be determined by nitrogen adsorption using the BET method (according to: Janssen et al, Journal of Applied Polymer Science 52, 1913, 1994).
  • Bioactivity or "bioactive material” is known in the field and relates to the effect of a material upon a living organism. A specific manifestation thereof is “biomnieralisation” . Briefly, biomineralisation refers to the ability of a material to induce calcium phosphate deposition on the surface of the object when placed in fluids. These fluids can be but are not limited to simulated body fluid, phosphate buffered or unbuffered physiological sodium chloride solution and the fluid in a living organism.
  • Biodegradation or “biodegradability” is known in the field. Briefly, the term is used herein to relate the degradation of materials by humidified atmospheres and/or by liquid at various temperatures and/or cellular action. The characteristic parameter for the degradation is the mass loss of the material and/or the reduction in molecular weight of the applied material.
  • Primary Particle is known in the field: Briefly the term relates to particles in the nanometer scale, such particles are often termed “nanoparticles”. Suitable are particles between 5 - 200 nm, preferably 5 - 90 nm , particularly preferably 5 - 20 nm. Such particle size results in material having a high surface area (e.g. > 30 m 2 /g).
  • Nanoparticles in the context of this invention, comprise primary particles and secondary particles.
  • the term secondary particle includes such particles which are formed by interaction of primary particles. These secondary particles can be significantly larger than primary particles. Secondary particles can be formed by primary particles attached to each other by physical forces, such as Van-der-Waals forces, or by individual primary particles grown together which have solid necks between the individual primary particles and can be formed by Oswald ripening or sintering / annealing. The 3-D fractal dimension of the secondary particles can vary over a wide range from just above 1 to nearly 3.
  • coating is known in the field. Briefly, the term is used herein to describe a covering that is applied to a substrate, i.e. the surface of an object.
  • a coating as used herein, may cover the substrate completely or only parts thereof.
  • bioactive glass is known in the field. Briefly, the term is used herein to describe a group of surface reactive, glass-ceramic containing biomaterials and include the original bioactive glass, Bioglass 45S5, but also bioactive glass 42S5, S53P4, 55S4, 58S, 70S30C, 45S5F, 40S5B5 and others. As described in further detail below, the term bioactive glass includes Si02 containing glass- ceramic materials which further comprise CaO and / or SrO. Thus, in the context of this invention, Ca of the bioactive glass may be replaced partly or in full by Sr. The present invention will be better understood by reference to the figures.
  • Nanoparticles (21) first group; (22) second group, (23) third / further group of nanoparticles
  • Precursor solution (71) precursor solution for first group; (72) precursor solution for second group, (73) precursor solution for third / further group of nanoparticles.
  • Flame spray pyrolysis allows the production a wide spectrum of metal oxides from inexpensive metal salts.
  • Fig. 1 shows in sections A, C and D various embodiments for a suitable set-up to manufacture the inventive coatings and devices.
  • section B various embodiments of the nanoparticles are shown:
  • Fig. 2 schematically represents an implant (4), in the form of an implant screw for dental applications, having a first and a second coating ((11) and (12)) as well as a non- coated surface (3); schematically shown are regions of hard tissue (ht), soft tissue (st) and for the crown of the implant (cr)
  • Fig 3 Atomic force micrographs of the uncoated and coated Ti-disk showing deposition of nanoparticles on an implant surface according to examples #0 - #4. a) uncoated, ex#0 . b)ceria coated, #1. c) bioglass coated, #2. d) BG/ceria coated, #3. e) Zn2-SrBG/ceria coated, #4.
  • Fig. 4 Secondary electron micrographs of nanoparticle coatings on Ti substrates. A trench was introduced by focused ion beam and the coatings were imaged from the side .
  • Fig. 5 Standardized abrasion measurements on the coated implants.
  • X-axis no. of cycles;
  • Y-axis m.% normalized to initial mass.
  • Fig. 6 Secondary electron micrographs of a bioglass-coated Ti substrate according to #2; scale bar shows 10 micrometer
  • Fig. 7 Cytotoxicity against gingival human fibroblasts of the inventive coatings (3 rd to 6 th bar); the toxic surfactant Triton X was used as a positive control (1 st bar) and non- toxic dPBS buffer as a negative control (2 nd bar). Y-axis normalized to controls, shown in %.
  • Fig. 8 Antibacterial activity against methicillin- resistant Staphylococcus aureus (MRSA). Y-axis normalized to negative control, shown in %.
  • Fig. 9 Bacterial growth on the different implant surfaces. An MRSA culture was first incubated on top of the disks and then left to grow further in absence of the disks.
  • the invention relates to a structured coating (1) which is defined by its chemical composition (i.e.
  • the invention provides for a structured coating (1) comprising Bioglass (preferably 5- 100 wt%) as a first group of oxidic material and optionally ceria (preferably a 0-95 wt%) as a second group of oxidic material, wherein the coating comprises a plurality of agglomerated nanoparticles (2) of said first and second group of oxidic material (21, 22); and wherein said nanoparticles (2) having a mean particle diameter of 5 - 200 nm of Ra as determined by electron microscopy; and wherein the surface roughness of the coating is 100 - 800 nm of Ra as determined by atomic force microscopy and wherein the porosity of the coating is at least 60%, as determined by electron microscopy.
  • the structured coatings (1) as described herein are adapted to cover a substrate (3) partly or in full. This aspect of the invention shall be explained in further detail below:
  • the inventive coating comprises one or more chemical entities, whereby bioactive glass is a mandatory component (first group of oxidic material), ceria is an optional component (second group of oxidic material) and a third component may further be present.
  • bioactive glass is a mandatory component (first group of oxidic material)
  • ceria is an optional component (second group of oxidic material)
  • a third component may further be present.
  • the chemical composition of the inventive coatings may vary over a broad range. This is considered a significant benefit, as the coating may be adapted (or tailored) to the need of a specific implant.
  • the inventive coating comprises, particularly consists of, bioglass. Accordingly, the inventive coating may comprise up to 100 wt% bioglass.
  • the inventive coating comprises, particularly consists of, a combination of both, bioactive glass and ceria. Accordingly, the inventive coating may comprise less than 100 wt% bioglass and more than 0 wt% ceria. In an advantageous embodiment, the invention relates to a coating comprising 20-90 wt%, such as 30-80 wt% bioglass and 10-80 wt%, such as 30-70, wt% ceria.
  • the inventive coating comprises, particularly consists of, a combination of three chemical entities, bioactive glass, ceria and a third component.
  • the inventive coating may comprise less than 100 wt% bioactive glass, more than 0 wt% ceria and more than 0 wt% of said third component.
  • Such third component may comprise oxidic material functioning as a connective layer, such as zirconia.
  • Such third component may further comprise zinc. Said third component may amount to up to 90 wt%.
  • the invention relates to a coating comprising 20-90 wt%, such as 30-80 wt% bioactive glass, 5-75 wt%, such as 10-60 wt% ceria and 5-75 wt%, such as 10-60 wt% of said third component.
  • the invention relates to a coating comprising 49 wt.% bioactive glass (45wt% SiO2, 6% wt% P205, 24.5 wt% Na20; 12.25 wt%, SrO 12.25 wt% CaO), 49 wt% ceria and 2 wt% Zn.
  • additional oxides include, but are not limited to, sodium oxide, calcium oxide, phosphorous oxide, aluminium oxide, boron oxide, strontium oxide, potassium oxide, magnesium oxide or combinations and mixtures thereof.
  • Bioglass contains (i.e. comprises or consists of) oxides of Si, Ca / Sr, Na and P and optionally further dopants.
  • the bioglass contains oxides of Si, Ca
  • the bioglass contains oxides of Si, Sr
  • the bioglass contains oxides of Si, Ca, Sr, Na and P and optionally further dopants.
  • Bioglass typically contains SiO2 in an amount of less than 66wt%, such as 20 - 60 wt%, preferably 30 - 50 wt%.
  • Bioglass typically contains CaO or SrO (as the case may be) in an amount of 10 - 50 wt%, preferably 20 - 40 wt%.
  • Bioglass typically contains Na20 in an amount of 5 - 50 wt%, preferably 15 - 30 wt%.
  • Bioglass typically contains P205 in an amount of 0 - 20 wt%, preferably 3 - 10 wt%. It is believed that P205 supports nucleation of calcium phosphate, which deposits on the surface; it is not considered essential.
  • Bioactive glasses distinguish from calciumphosphates in that (i) silica is present, (ii) the amount of sodium is higher (aqueous solutions thereof show a high ph value) and (iii) phosphorous is an optional component.
  • the ratio Ca:P (or Sr : P or (Ca+Sr) : P) in the inventive particle is in the range of 10:1 to 1:10.
  • the ratio Ca:Na (or Sr:Na or (Ca+Sr):Na) is in the range of 2:1 to 0.5:1.
  • Bioglass may further contain dopants ( "BG-dopants”), typically in an amount of less than 5 wt%. Suitable dopants include Ag, Cu, Ga, Zn and Co. Such BG-dopants may be present in metallic and / or oxidic form. Examples of Bioglass include types 45S5, 42S5, S53P4, 55S4, 58S, 70S30C, 45S5F, 40S5B5, all of them being known per se; chemical compositions may be taken from the following table:
  • Ceria (2 nd group of material) The material is known in the field and discussed in e.g. WO2004/005184.
  • ceria possesses antioxidative properties and neutralizes reactive oxygen species by mimicking the body's own enzymes. Additionally, ceria possesses antimicrobial properties .Without being bound to theory, it is believed that the above properties support wound healing and mitigate inflammation. In one embodiment, said ceria is selected from compounds of formula (I)
  • CeO 2-x (I) wherein x is between 0 and 0.67; and wherein up to 10 wt% of Ce may be replaced by a dopant metal ion.
  • said ceria is nonstoichiometric cer (IV)oxide; 0.2>x>0. It may be crystalline (with crystal defects) or amorphous, preferably crystalline.
  • said ceria (stoichiometric or non- stoichiometric) may contain dopants ("ceria-dopants"). Suitable dopants are known in the field and include Zr, Zn, Cu, Ag and Ga, preferably Zr. Such Ceria-dopants may be present in metallic and / or oxidic form. The amount of Ceria-dopant may vary over a broad range, typically below 10 wt%.
  • stoichiometric and non- stochiometric ceria is covered. This also includes surface defects which are observed for nanoparticulate material, particularly when obtained by an FSP process.
  • zirconia may be identified as a third component (23).
  • a zirconia- rich region of the inventive layer functions as a connective component towards a substrate (as defined below) while a bioglass/ceria rich region functions as a connective component towards tissue.
  • the architecture may be specified on various levels: macroscale, nanoscale and single unit.
  • a. Macroscale On a macroscale, the substrate may be coated differently. In one embodiment, two or more sections (e.g. two sides) of the substrate ' s surface are differently coated; In one alternative embodiment, the substrate ' s surface is coated with a coating showing a gradient e.g in thickness and or in chemical composition. In one further embodiment, the substrate's surface is coated with a patterned coating (e.g. showing a pattern coated / non- coated or showing a pattern of its chemical composition). Such variation of the coating on a macroscale results in implants where different tissues experience different surfaces. This finds use for example in tooth implants where one side is anchored in soft tissue (gum) and the other in bone (tooth).
  • Nanoscale The nanostructure of the surface has a specific topography, porosity and roughness.
  • the inventive coating comprises a plurality of nanoparticles that are partly or fully agglomerated. While the particles produced during the inventive process (the flame spray pyrolysis described below as step (c)) are primarily or exclusively "primary particles", they become partly or fully “agglomerated” upon formation of a coating (the coating process described below as step (d)). Primary particle size is as discussed above, preferably around 5- 20 nm, but they are at least partly sintered to form agglomerated particles.
  • the surface roughness of the coating is 100 - 800 nm, preferably 150-400 nm as determined by AFM; and / or
  • the particle size is 5-90 nm, such as 5-20 nm as determined Electron Microscopy; and / or In one embodiment, the thickness of the coating is 200 - 10000 nm, preferably 1000 - 5000 nm, as determined by
  • the porosity of the coating is >60%, preferably >70%, much preferably ⁇ 75%, as determined by electron microscopy.
  • Single unit The single units of the coating
  • nanoparticles agglomerated nanoparticles, (2)
  • nanoparticles have complex architectures themselves and combine properties on the nanoscale. They consist of multiple metal-oxide phases (e.g. bioglass and ceria) in different arrangements (pure, core-shell, janus types). Additionally, they contain dopant ions dispersed in their main materials. This situation is visualized in Fig. 1B. Accordingly, the invention provides for a coating wherein said first group of oxidic material and said second group of oxidic material (i) are present as separate nanoparticular entities or (ii) are present as combined nanoparticular entities (including core-shell particles and janus-type particles).
  • the inventive coating comprises particles having a narrow primary particle size distribution.
  • the distribution of the particle diameter is evaluated by measuring the particle diameters of at least 200 individual, representative particles from transmission electron micrographs. The particle size distribution is then fitted by a log-normal distribution (see Grass and Stark, Journal of Materials Chemistry 2006 Vol. 16, P 1825 ff). The distribution is characterized as narrow if the geometric standard deviation of the measured and fitted distribution is below 1.9, more preferably below 1.7 and most preferably below 1.5.
  • a narrow size distribution as described above, improves the quality of the material and simplifies the uses disclosed herein.
  • Particle size may vary for the 1 st , 2 nd and 3 rd group of material. This will result in a mono-modal or bimodal or three-modal size distribution.
  • the coatings described herein have beneficial biochemical properties, they are useful in in medical applications, particularly for coating of implants
  • the invention thus also provides for the use of a coating as described herein in the manufacture of an implant for the treatment of hard tissue of a mammal, particular a human; or (ii) the treatment of soft tissue of a mammal, particularly a human; or (iii) the combined treatment of hard and soft tissue of a mammal, particularly a human.
  • the invention relates to implants (4) comprising a substrate (3) having one or more structured coatings (1) as described herein which coated at least partially thereon.
  • the coatings described herein have beneficial biochemical properties, they are useful in in medical applications, particularly for coating of implants. This aspect of the invention shall be explained in further detail below:
  • Implant The term is known in the field and particularly relates to a device that is placed inside or on the surface of the body. Many implants are prosthetics, intended to replace missing body parts. Other implants deliver medication, monitor body functions, or provide support to organs and tissues. For teeth for example, the screw that goes into the gum is considered an implant whereas the crown is considered a prosthesis.
  • Inventive implants (4) comprise a substrate (3) and are partly or fully coated with a coating (1) as described herein. It is understood that an implant is a man-made device, thereby distinguishing from a transplant, which is a transplanted biomedical tissue.
  • an implant is preferably a device which is anchored in tissue and thus termed medical implant.
  • the term medical implant thus refers to a device fully surrounded by tissue or partly surrounded by tissue.
  • Examples of medical implants include dental implants (e.g. the above screw), artificial hip joints, cardiatic stimulators.
  • implants contain electronics (such as an artificial pacemaker) or pharmaceutically active ingredients .
  • the substrate contains a material known in the field, including metals, such as titanium and its alloys, iron alloys, and ceramics, such as zirconia.
  • the substrate may be pre-treated, e.g. etched, polished or pre-coated.
  • a pre-coated substrate is preferred in case the inventive coating consists of first group of oxidic material (21) or consists of first and second group of oxidic material (21, 22). (ie. no third component (23).
  • a non-coated substrate may be used in case the inventive coating consists of (21) and (23) or (21), (22) and (23).
  • Coating The coating of an implant is known per se, it includes partial and full coating, as well as mono-layer and multi-layer coating.
  • the substrate ' s surface is completely coated with a coating as described herein ("full coating”). In one embodiment, the substrate ' s surface is partly coated with a coating as described herein ("partial coating”). Accordingly, in one embodiment, the structured coating (1) is present on less than 50% of the substrate's surface or the structured coating is present on more than 90% (preferably 100%) of the substrate ' s surface.
  • the coating is a mono-layer coating.
  • a mono-layer is a layer having the same chemical composition along a line perpendicular to the substrate ' s surface.
  • the coating is a multi-layer coating.
  • a multi-layer is a coating where the chemical composition varies along a line perpendicular to the substrate ' s surface.
  • any one of the parameters particle size, roughness, thickness, porosity varies over the implant ' s surface.
  • the inventive coating acts as a connective layer between substrate and tissue, allowing for a time-dependent dissolution / reorganization of the implants top layer(s).
  • a implant ' s top layer may dissolve over time allowing direct contact of tissue with a lower
  • the implant is free of intermediate layers between substrate (3) and structured coating (l).
  • the implant is free of additional layers on top of the structured coating (1).
  • an implant as described herein characterized in that (i) the chemical composition of the structured coating (1) varies over the implants surface (x-axis, y-axis); and / or (ii) the chemical composition of the structured coating (1) varies over the coating thickness of the coating (z-axis, the z- axis being an axis perpendicular to the implant surface).
  • the invention relates to an implant described herein adapted to (i) the treatment of hard tissue of a mammal, particular a human being; or (ii) the treatment of soft tissue of a mammal, particularly a human being; or (iii) the combined treatment of hard and soft tissue of a mammal, particularly a human being.
  • the invention also provides for the use of an implant as described herein in the above treatments (i), (ii) and (iii).
  • the invention provides for a method of using an implant as described herein in the above treatments (i); (ii); and (iii) in a subject in need thereof .
  • the invention relates to an implant described herein adapted to dental applications in a human. Accordingly, the invention also provides for the use of an implant as described herein in dental applications. Further, the invention provides for a method of using an implant as described herein in dental applications in a subject in need thereof.
  • inventive coatings due to their unique chemical composition and morphology, exhibit different properties that increase the success rate of implantations. Fist, better cell attachment on the implant allows for better resorption. Second, decreased foreign body reaction and inflamination results in better acceptance of the body. Third, a higher cytocompatibility is observed. Forth, formation of biofilms on the implant is prevented. This prevention is governed by contact of bacteria with the nanoparticulate coating.
  • the invention in a third aspect, relates to a process for manufacturing a coating and / or an implant as described herein.
  • the inventive method combines FSP synthesis of bioglass and ceria and its direct coating on a substrate.
  • the inventive manufacturing process is a one-step process in which one or more solutions (71, 72) are sprayed and ignited and the thus formed nanoparticulate material (21, 22) is directly deposited on a substrate (3) to form a coating (1).
  • the invention provides for the manufacturing of a coated implant (4) as described herein, the method comprising the steps of:
  • Step (a) substrate:
  • the substrate to be coated may be provided in a fixed position or in a movable position. It may be beneficial to adjust distance between flame and substrate. Such adjustment may affect agglomeration of the nanoparticles and bonding to the surface.
  • the substrate may be beneficial to allow rotational movement of the substrate and / or longitudinal movement of the substrate. This may allow selective coating (such as partial or full coating, one or more layers) of the substrate .
  • step (a) comprises providing as substrate (3) and means for contact cooling. Such cooling improves step (d) in that sintering of the nanoparticulate material on the substrate is controlled.
  • the substrate may native or may be pre treated. Pre-treatment may increase surface roughness, e.g. by etching or sandblasting.
  • Step (b) precursor solutions:
  • the starting material for step (c) is provided in the form of one or more solutions comprising one or more metal / phosphor precursors and one or more solvents.
  • precursor solutions are combustible.
  • Suitable solvents (including combination of solvents) have a net heat of combustion of > 15 kJ/g, preferably > 20 kJ/g, more preferably > 23 kJ/g. This may be achieved by providing an organic solvent or a mixture of organic solvents with a mean number of carbon atoms of > 2 C atoms, usually at least 2.2 C atoms, preferably at least 3 C atoms, more preferably about 4 to 10 C atoms.
  • Suitable solvents may be selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, ethers, esters, and carboxylic acids .
  • the precursor solution has a viscosity of
  • step (c) This low viscosity, such as 0.3 - 100 mPas, facilitates step (c).
  • Suitable precursor compounds for the use in the method of the present invention are compounds that are soluble in a solvent as outlined above.
  • organic groups comprising salts are preferred, in particular purely organometallic compounds or organometalloid compounds such as a salt of at least one (optionally substituted) carboxylic acid, such as acetic acid, formic acid, but also dicarboxylic acid, oligocarboxylic acid and/or polycarboxylic acid and/or other common organometallic or organometalloid ligands such as acetylacetonate, tetramethylacetoacetonate, ethylene diamine and others, optionally as hydrate.
  • organometallic compounds or organometalloid compounds such as a salt of at least one (optionally substituted) carboxylic acid, such as acetic acid, formic acid, but also dicarboxylic acid, oligocarboxylic acid and/or polycarboxylic acid and/or other common organometallic or organometalloid ligands
  • the salt may also be produced within the solvent mixture in situ, meaning that a suitable salt precursor (namely a metal comprising compound, e.g. an oxide, a carbonate or a pure metal, that reacts with at least one of the compo ⁇ nents of the solvent to form a solution) is brought into the solvent mixture where it then forms the salt or derivative of the solvent (e. g. a carboxylic acid salt of a carboxylic acid from the solvent).
  • a suitable salt precursor namely a metal comprising compound, e.g. an oxide, a carbonate or a pure metal, that reacts with at least one of the compo ⁇ nents of the solvent to form a solution
  • the salt or derivative of the solvent e. g. a carboxylic acid salt of a carboxylic acid from the solvent.
  • said one or more precursor solutions contain
  • one or more soluble silica precursors such as hexame- thyldisiloxane, tetraethoxysilane or any other organo- silicon compounds;
  • soluble sodium precursors such as sodium 2- ethylhexanoate or any kind of soluble sodium source such as sodium carboxylate;
  • soluble calcium precursors such as calcium 2-ethylhexanoate or any kind of soluble calcium source such as calcium carboxylate
  • soluble strontium precursors such as Sr 2-ethylhexanoate or any kind of soluble Sr source such as Sr carboxylate
  • soluble phosphorous precursors such as tributyl phosphate or any other soluble phospho ⁇ rous source such as organophosphorous compounds
  • bioglass- dopants such as BG-dopants described herein;
  • soluble ceria precursors such as actetate, acetylacetonate, 2-ethylhexanoate or any other organo- cer compound
  • soluble precursors for ceria- dopants such as 2-Ethylhexanoates or acetates of zinc, strontium, copper, silver, gallium
  • soluble zirconia precursors such as actetate, acetylacetonate, 2-ethylhexanoate or any other organo-zirconium compound.
  • Step (c) Flame Spray Pyrolysis: FSP is a process known per se and described in the above named documents, WO2004/005184 and WO2011/020204. FSP processes are used in industry; they are reliable and scalable. Briefly, nanoparticulate metal oxides are obtained by this method in that the precursor solution of step (b) is formed into droplets and flame oxidized, optionally in the presence of an oxidizing gas. By using multiple spray or flames, as explained below and shown in the figures, complex geometries and architectures of both the nanoparticles and the coatings are obtained.
  • the thus obtained nanoparticulate material are directly ("in situ") brought into contact with a substrate, step (d) below, thereby forming a coating on said substrate.
  • the flame has a temperature of at least 1000°C, usually at least 1500°C, preferably at least about 2000°C. ⁇ preferred range of the flame temperature for many applications is 1600 to 2600°C.
  • Droplets Droplets are typically formed by way of one or more spray nozzles. The average diameter of the droplets may vary depend on the liquid dispersion setup and the properties of the liquid itself. Usually, the average droplet diameter ranges from 0.1 ⁇ m to 100 ⁇ m, preferably from 1 ⁇ m to 20 ⁇ m.
  • Oxidizing gas Suitable gases are known in the field, pre- mixed methane / oxygen or separate feeds of air and methane may be used.
  • the distance flame nozzle - substrate may be adjusted according to the specific requirements of the process. Typically, 2-100 cm, such as 5-50 cm, are a suitable range.
  • Step (d) Coating The as obtained nanoparticulate material (bioglass, ceria and optional third component) are directly (in situ) coated on a substrate.
  • Such in situ deposition in conjunction with the stoichemetric formation of said nanoparticulate material, allows full control over particle composition at different times and thus thicknesses and architecture of the inventive coating. may be subject to a simultaneous coating (c.f. fig.%) or a subsequent coating (stepwise coating, fig. ). This allows realizing complex geometries and architectures of the inventive coatings.
  • the substrate ' s temperature is controlled, depending on the substrate ' s material and the coating. Typically, the temperature is in the range of 100 °C to 1500 °C. For metallic substrates, 100 - 800°C is preferred, for ceramic substrates 500 - 1500°C is preferred.
  • Step (e), post-treatment Post-treatment steps are optional and known in the field.
  • the implant obtained in step (d) is subjected to annealing. Annealing may influence agglomeration of nanoparticles.
  • the implant obtained in step (d) is subjected to ultra-sonication Ultra-sonication may influence porosity of the coating.
  • Product-by-Process In a further embodiment, the invention relates to coatings and implants as disclosed herein which are obtainable by, or obtained by, a method as described herein .
  • All particles were produced by liquid-feed flame spray pyrolysis.
  • the precursors were dissolved in the respective solvents (2-Ethylhexanoic acid: 2-EHA, Tetrahydrofuran: THF) such that the total metal ion concentration of the solution was 0.4 M.
  • 5 mL/min precursor solution was pumped to a water-cooled spray nozzle and dispersed by 5 L/min 02. The pressure drop at the nozzle tip was approximately 1.5 bar.
  • the precursor aerosol was ignited by premixed
  • Particles were either collected on a glass fiber filter mounted approx. 70 cm above the nozzle to obtain bulk material of the particles or on a titanium disk mounted approx. 8 cm above the nozzle to obtain the inventive coating.
  • Bioglass and ceria hybrid particles Mixture of equal volumes of Bioglass and ceria precursor as described above.
  • the Ti substrate was replaced by Yttrium-stabilized zirconia.
  • the results obtained with such substrate are comparable to the here described results with Ti.
  • the Dyn190Al cantilever was operated at a frequency of 190 kHz, with a force constant of 48 N/m. Image analysis was conducted using Gwyddion.
  • the results are shown in fig. 3.
  • the micrographs show a well distributed layer of agglomerated nanoparticles on the surface of the Ti substrate. Coating roughness (calculated from the AFM data shown in Fig. 3) and contact angle of the thus obtained coatings are provided in the table below.
  • the scanning electron micrographs were acguired using FEI Helios 660 G3 UC FIB/SEM (10 kV, 0.4 nA) equipped with an in-column detector (ICD). Trenches were cut by a focused gallium ion beam. The subsequent images were acquired using an ICD using 5 kV acceleration voltage and 0.1 nA electron beam current.
  • Example #3 are shown in fig. 4.
  • the cross- section shows a stable, yet porous coating on top of the Ti substrate with an average thickness of around 4 ⁇ m. Coating thickness is controlled by deposition time and precursor metal ion concentration.
  • Taber Abrader (Model 5135, Taber, North Tonawanda, NY) was used to test abrasion.
  • the applied weight was 1 kg at 60 rpm sample rotation.
  • the abrasive material, a S42 sandpaper strip was wrapped around CS-0 rubber wheel (Taber, North Tonawanda, NY).
  • SEM scanning Electron Microscopy
  • EDX Energy Dispersive X-ray
  • example #2 The results of example #2 are shown in fig. 6. There are evident changes in micro-morphology between the three time points (4 hours, 1 day, 1 week). The bioglass mineralizes on top of the implant, an effect that supports integration into bone.
  • HUV-EC-C a human umbilical endothelial cell line
  • PromoCell Endothelial Cell Growth Medium 2 supplemented with 2% of the PromoCell Endothelial Supplement Mix.
  • the Normal Human Dermal Fibroblasts (NHDF) cell line and the primary Human Gingival Fibroblasts (HGF) were both cultured using Dulbecco's Modified Eagle's Medium, high glucose, (Invitrogen) supplemented with 10% fetal calf serum (Invitrogen) and 1% penicillin, streptomycin and neomycin (Invitrogen) .
  • NHDF Normal Human Dermal Fibroblasts
  • HGF Human Gingival Fibroblasts
  • Cells were cultured at 37°C and 5% CO2.
  • Cytotoxicity was assessed by measuring lactate dehydrogenase (LDH) release using CytoTox 96® Non- Radioactive Cytotoxicity Assay (Promega). After cell seeding, 50 ⁇ L of the medium were mixed with 50 pL of the LDH detection reagent in a 96-well plate. After 30 minutes, the absorbance of the plate was read in a Mithras plate reader at 490 nm .
  • LDH lactate dehydrogenase
  • the results are shown in fig. 7.
  • the toxic surfactant Triton X was used as a positive control and non-toxic dPBS buffer as a negative control. While all coatings show low toxicity, the addition of ceria and strontium to the coating significantly improve compatibility. Compatibility with gingival human fibroblasts indicates good prospects for implant integration into the gums (gingiva). Additionally, the improved adhesion of fibroblasts has been seen in confocal microscopy.
  • OD600 optical density at 600 nm
  • TSB100 containing no bacteria was used as a control experiment on the implants. After incubation for 2.5 h at 37 °C and 160 rpm, 100 ⁇ L of each supernatant was collected and diluted 104 times. 100 ⁇ L of the diluted suspensions were plated on a count agar dish and incubated at 37 °C until colonies were countable. Colony forming units (CFU) were quantified using the SCAN® 300 with SCAN® Software. The results are shown in fig. 8: Antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) was measured. Whereas the uncoated and the bioglass-coated disks show no antibacterial activity, the incorporation of ceria into the coating significantly reduces bacterial growth. Infections are common after implantation and can lead to drastic consequences. The prevention of biofilm formation is pivotal to implantation success and has been achieved here by incorporating ceria into the coating.
  • Cells were fixed either with a 4% parafolmadehyde solution or a fixation solution containing 4% parafolmadehyde, 65 mM PIPES, 25 mM Hepes, 10 mM EGTA, 3 mM MgC12 for 20 minutes. After fixation, cells were permeabilized using a 0.1% Triton X solution for 10 minutes. Cells were stained for actin and nuclei, using Alexa488-phalloidin (1:250, Thermo Fischer) and DAPI (1:1000, Thermo Fischer).
  • bacteria were diluted to an optical density at 600 nm (OD600) of 0.1 and grown for 1.5 h, toreassure that the bacteria were in the log phase.
  • a serial dilution was made (100, 10-1, 10-2, 10-3) in PBS and spotted in triplicates (20 ⁇ l each) onto a PC agar plate. Additionally, 20 ⁇ l of each dilution were added to 180 ⁇ l of TSB30Glc in a 96 well plate and sealed with a gas-permeable membrane Breathe-easy® (Z380059, Sigma Aldrich) . Optical density curves at 600 nm were recorded for 24 h while shaking. The PC agar plates were incubated at 37 °C until colonies were countable. Colony-forming units (CFU) were quantified using the SCAN® 300 with SCAN® Software .
  • #0 - uncoated disk control
  • #1 - coated with bioglass as described above #2 - inventive, coated with bioglass / ceria as described above
  • #3 - inventive coated with Zn2- Sr bioglass / ceria as described above
  • #4 - surface treated uncoated disc considered gold standard commercial product SLA Fa. Straumann,).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Ceramic Engineering (AREA)
  • Dispersion Chemistry (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention concerne de nouveaux revêtements et leurs utilisations, ainsi que des procédés de fabrication de tels revêtements. Les revêtements sont caractérisés par leur composition chimique et leur architecture ; ils agissent comme antimicrobiens, régénérateurs tissulaires et liants tissulaires, d'où leur utilité en tant que revêtement d'un implant. Des procédés de fabrication pour un tel revêtement combinent une pyrolyse par pulvérisation de flamme et un revêtement direct d'un substrat ; le procédé utilise des matériaux de départ peu coûteux et peut être mis à l'échelle.
PCT/EP2020/084301 2019-12-13 2020-12-02 Implants revêtus et leurs procédés de fabrication Ceased WO2021115882A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP19216118.0A EP3834853A1 (fr) 2019-12-13 2019-12-13 Revêtements, implants revêtus et procédés de fabrication correspondants
EP19216118.0 2019-12-13

Publications (1)

Publication Number Publication Date
WO2021115882A1 true WO2021115882A1 (fr) 2021-06-17

Family

ID=68917319

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/084301 Ceased WO2021115882A1 (fr) 2019-12-13 2020-12-02 Implants revêtus et leurs procédés de fabrication

Country Status (2)

Country Link
EP (1) EP3834853A1 (fr)
WO (1) WO2021115882A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114246993B (zh) * 2021-12-09 2023-09-01 中国科学院宁波材料技术与工程研究所 一种活性成分释放性能可调的复合涂层及其制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005184A1 (fr) 2002-07-03 2004-01-15 Eidgenössische Technische Hochschule Zürich Oxydes metalliques prepares par pyrolyse par projection a la flamme
US20050176843A1 (en) 2004-02-06 2005-08-11 Peter Burtscher Dental composites based on X-ray-opaque mixed oxides prepared by flame spraying
WO2005087660A1 (fr) 2004-03-15 2005-09-22 Eidgenössische Technische Hochschule Zürich Synthese de flamme de nanoparticules de sel metallique, notamment des nanoparticules renfermant du calcium et du phosphate
WO2011020204A1 (fr) 2009-08-19 2011-02-24 ETH Zürich Matériaux en verre bioactifs radio-opaques
WO2017031524A1 (fr) 2015-08-25 2017-03-02 The Australian National University Revêtements poreux
WO2017062573A1 (fr) 2015-10-06 2017-04-13 University Of Central Florida Research Foundation, Inc. Implant et revêtement pour réduire l'ostéolyse

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005184A1 (fr) 2002-07-03 2004-01-15 Eidgenössische Technische Hochschule Zürich Oxydes metalliques prepares par pyrolyse par projection a la flamme
US20050176843A1 (en) 2004-02-06 2005-08-11 Peter Burtscher Dental composites based on X-ray-opaque mixed oxides prepared by flame spraying
WO2005087660A1 (fr) 2004-03-15 2005-09-22 Eidgenössische Technische Hochschule Zürich Synthese de flamme de nanoparticules de sel metallique, notamment des nanoparticules renfermant du calcium et du phosphate
WO2011020204A1 (fr) 2009-08-19 2011-02-24 ETH Zürich Matériaux en verre bioactifs radio-opaques
WO2017031524A1 (fr) 2015-08-25 2017-03-02 The Australian National University Revêtements poreux
WO2017062573A1 (fr) 2015-10-06 2017-04-13 University Of Central Florida Research Foundation, Inc. Implant et revêtement pour réduire l'ostéolyse

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ALTOMARE L ET AL: "Microstructure and in vitro behaviour of 45S5 bioglass coatings deposited by high velocity suspension flame spraying (HVSFS)", JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE, KLUWER ACADEMIC PUBLISHERS, BO, vol. 22, no. 5, 3 April 2011 (2011-04-03), pages 1303 - 1319, XP019910212, ISSN: 1573-4838, DOI: 10.1007/S10856-011-4307-6 *
GRASSSTARK, JOURNAL OF MATERIALS CHEMISTRY, vol. 16, 2006, pages 1825 ff
JANSSEN ET AL., JOURNAL OF APPLIED POLYMER SCIENCE, vol. 52, 1994, pages 1913
KOKUBO: "Handbook of biomineralization", 2007, WILEY
MARTIN T. MATTER ET AL: "Engineering the Bioactivity of Flame-Made Ceria and Ceria/Bioglass Hybrid Nanoparticles", ACS APPLIED MATERIALS & INTERFACES, vol. 11, no. 3, 20 December 2018 (2018-12-20), US, pages 2830 - 2839, XP055705250, ISSN: 1944-8244, DOI: 10.1021/acsami.8b18778 *

Also Published As

Publication number Publication date
EP3834853A1 (fr) 2021-06-16

Similar Documents

Publication Publication Date Title
Zhu et al. Advances in implant surface modifications to improve osseointegration
Xue et al. Surface modification techniques of titanium and its alloys to functionally optimize their biomedical properties: thematic review
Zheng et al. Ag modified mesoporous bioactive glass nanoparticles for enhanced antibacterial activity in 3D infected skin model
Mokhtari et al. Chitosan-58S bioactive glass nanocomposite coatings on TiO2 nanotube: Structural and biological properties
Kumar et al. Fabrication and characterization of ZrO2 incorporated SiO2–CaO–P2O5 bioactive glass scaffolds
CN101791436B (zh) 具有多孔磷酸钙-壳聚糖复合涂层的生物医用材料
CN102014976A (zh) 涂层和涂覆方法
JP7583848B2 (ja) インプラント及び他の基材用のジルコニウム及びリン酸チタンコーティング
Kung et al. Antibacterial activity of silver nanoparticle (AgNP) confined mesoporous structured bioactive powder against Enterococcus faecalis infecting root canal systems
EP3509650B1 (fr) Dispositifs médicaux implantables comportant une couche de revêtement ayant des propriétés antimicrobiennes à base d'hydroxyapatite nanostructurée
Furkó et al. Comparative study on preparation and characterization of bioactive coatings for biomedical applications—A review on recent patents and literature
Workie et al. Ion-doped mesoporous bioactive glass: Preparation, characterization, and applications using the spray pyrolysis method
Chen et al. Surface functionalization of 3D printed Ti scaffold with Zn-containing mesoporous bioactive glass
D’Agostino et al. Mesoporous zirconia surfaces with anti-biofilm properties for dental implants
Sheykholeslami et al. Synthesis and development of novel spherical mesoporous SiO2/HA particles and incorporating them in electrodeposited hydroxyapatite coatings for biomedical applications
Bakitian A comprehensive review of the contemporary methods for enhancing osseointegration and the antimicrobial properties of titanium dental implants
WO2021115882A1 (fr) Implants revêtus et leurs procédés de fabrication
Chou et al. The effect of Ag dopants on the bioactivity and antibacterial properties of one-step synthesized Ag-containing mesoporous bioactive glasses
Durgalakshmi et al. Structural, morphological and antibacterial investigation of Ag-impregnated Sol–Gel-Derived 45S5 nanoBioglass systems
Maximov et al. Bioactive Glass—An Extensive Study of the Preparation and Coating Methods. Coatings 2021, 11, 1386
KR101353338B1 (ko) 생체 친화성 임플란트의 제조방법
KR20130009481A (ko) 표면 개질된 생체활성 유리 나노섬유 및 이의 제조방법
Lung et al. A Multi-Element-Doped Porous Bioactive Glass Coating for Implant Applications. Materials 2021, 14, 961
JP4815583B2 (ja) 無機粒子・酸化チタン複合体層の製造方法
Nasr-Esfahani et al. Bonding strength, hardness and bioactivity of nano bioglass-titania nano composite coating deposited on NiTi nails

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20815840

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20815840

Country of ref document: EP

Kind code of ref document: A1